Treatment-resistant depression (TRD) is generally defined as depression that has not responded to at least 2 adequate trials of antidepressant drugs from different pharmacological classes.1 Other more stringent definitions might also require the failure of 1 or 2 augmentation strategies (eg, lithium [Eskalith, Lithobid] or thyroid augmentation of an antidepressant; or combination therapy using 2 different antidepressants).2 Depression might not be considered truly treatment-resistant unless a patient did not improve following antidepressant augmentation with an atypical antipsychotic agent, such as olanzapine (Zyprexa).3

Although TRD is defined in terms of a person's depression being resistant to medication, it usually also means that the patient has been unresponsive to whatever psychotherapy has been tried along the way. What might not be clear from the above but is known by all clinicians is that patients with TRD experience much internal suffering and misery; many of them are chronically suicidal, isolated, hopeless, desperate, unemployed, and frequently in and out of psychiatric hospitals. It is in this difficult-to-treat group of patients that various forms of brain stimulation therapy are now being tried.

Most TRD patients at some point receive electroconvulsive therapy (ECT), a procedure long known to be highly effective.4 However, ECT involves general anesthesia and it may disturb recent memory for a time, especially memory of events occurring on treatment days. The procedure unfortunately (and incorrectly) is perceived by many to be unsafe and/or damaging to the brain. High relapse/recurrence rates are also a problem, although maintenance ECT (an additional 1 or 2 treatment sessions at monthly intervals) is also possible. All that being said, ECT is probably underutilized.

Transcranial magnetic stimulationNew research findings suggest that other ways of stimulating the brain that do not involve ECT or induction of seizures may also be effective for treating persons with TRD. Repetitive transcranial magnetic stimulation (rTMS) is a new treatment involving stimulation of the brain with a magnetic field, administered daily for several weeks. It uses a new device—not yet approved by the FDA—for the treatment of depression. An intense magnetic field targets the prefrontal region of the brain, depolarizing neurons and generating pulses of electrical activity.

The short pulses of magnetic energy produced by a TMS device are aimed at the limbic system structures in the brain thought to control mood. The left prefrontal cortex is used to access these structures noninvasively from outside the brain using TMS. The magnetic energy passes through the skull into the brain without being distorted. This allows for a very focal type of stimulation, minimizing stimulation of nontargeted brain areas.

Once inside the brain, the dynamic (rapidly changing) nature of the magnetic pulses induces electrical charges to flow. The amount of electricity created in the brain is very small and cannot be felt by the patient, but these very small electric charges can cause the neurons to fire or become active. The objective of TMS is to stimulate (or activate) brain cells without causing a seizure. Patients remain awake and alert during the TMS procedure. Patients come in each weekday for 30- to 60-minute sessions (20 treatments over 4 weeks) and are able to drive home or return to work after each session.

A few studies directly comparing rTMS with ECT have been conducted. The 2 methods of brain stimulation have been found to be equally effective in treating nonpsychotic depressed patients, but rTMS was less effective than ECT in treating patients with psychotic depression.5 The major safety concern is the possibility of inducing unintended seizures, which can occur if applied magnetic fields are increased in intensity too rapidly or applied for too long.6 Other adverse effects reported occasionally include headache, facial muscle twitching, and tinnitus.7 Currently, rTMS is available only as an investigational treatment. One equipment manufacturer, Neuronetics,8 has recently completed patient enrollment for its series of clinical trials investigating TMS for the treatment of major depression. The trials are being conducted at multiple US and international locations and have enrolled more than 300 patient volunteers. The acute phase trial, which is randomized, double-blind, and sham-controlled, is designed to assess the safety and efficacy of TMS. An additional trial is designed to evaluate the durability of any positive TMS treatment effects.

Vagus nerve stimulationAnother way of stimulating the CNS is through the sensory afferent connections of the vagus nerve, which connects to many brain areas. Although the vagus nerve is better known for its parasympathetic efferent nerve connections to control autonomic functions, such as heart rate and gastric function, the vagus nerve contains 80% of afferent fibers carrying information to the brain from the head, neck, thorax, and abdomen. Vagus nerve stimulation (VNS) was first widely used for the treatment of resistant partial-onset seizures in epilepsy in the mid-1990s, and research has shown that the technique works well for that purpose. It also seems quite safe, with data available from more than 29,000 patients treated with VNS for refractory epilepsy.9

In VNS, an electrical device the size of a stopwatch is implanted in the chest underneath the skin. Two thin wires coming from the device wrap around the vagus nerve in the neck, sending regular pulses of electrical energy through the vagus nerve to the brain. Implantation is an outpatient procedure. The dose of stimulation can be modulated starting with low levels and proceeding upward if necessary.

Possible stimulation of the vagus nerve as therapy for patients with TRD is a relatively recent phenomenon; it was noted that patients who were treated for epilepsy with VNS reported positive mood effects independent of the degree of seizure control.10 Subsequently, it was found that VNS increases the cerebrospinal fluid concentrations of neurotransmitters or their metabolites such as γ-aminobutyric acid (GABA),11 and 5-hydroxyindoleacetic acid.12 VNS also affects the functional activity of known mood-regulating brain sites, such as the orbital frontal cortex, insula, thalamus, hypothalamus, cingulate, and hippocampus.13 Of course, it is also well known that several anticonvulsants (eg, lamotrigine [Lamictal], valproate [Depakote], and carbamazepine [Carbatrol, Tegretol]) also positively impact mood disorders.

On July 15, 2005, the FDA announced approval of VNS as long-term adjunctive treatment for patients 18 years or older with chronic or recurrent treatment-resistant depression based on the results of a clinical study of more than 200 patients conducted in the United States. During the first 3 months of therapy, patients who had the device implanted and turned on did not show any significant advantage in response compared with patients in whom the device was implanted but not turned on. There was a general pattern of increasing response rates observed over time.

At 1 year, approximately 2 to 3 of every 10 subjects had a clinically significant improvement in symptoms of depression with about half having almost no remaining depressive symptoms. Many of the patients who had a significant response within the first year of treatment continued to have a similar degree of response for 2 years.14

The FDA indication requires 4 or more adequate dose-duration trials of antidepressant treatments before trying VNS therapy. The FDA indication also requires that the patient must currently be experiencing a major depressive episode. Hence, under these guidelines it would not be appropriate to prophylactically treat a patient (while euthymic) with VNS therapy, even if the patient had a history of frequently recurring depression. Furthermore, although the device was effective in bipolar depression as well as resistant unipolar depression,15 as with any antidepressant treatment, there is concern over the possibility of patients undergoing bipolar "switch"—causing depressed patients to become manic. During the large multicenter trial, 6 hypomanic or manic reactions were identified according to DSM-IV criteria or the Young Mania Rating Scale. Five were observed in subjects with a known history of prior hypomanic or manic episodes.16 In all cases, the hypomanic or manic symptoms resolved either without intervention or with adjustment of the device and/or medications.

The vagal nerve stimulator does require surgery to implant it (a procedure similar to implanting a pacemaker in a pouch in the left chest wall), with an approach to the left vagus nerve in the neck to attach the lead.17 The device itself costs approximately $12,000 with the accompanying surgery adding perhaps another $15,000.18 Battery life is 6 to 9 years. Adverse effects may include voice alteration, hoarseness, cough, shortness of breath, a prickling sensation on the skin, or a tickling in the throat. VNS may be used in combination with antidepressant medications or with electroconvulsive therapy. As of September 2006, 1800 patients with TRD have started treatment with VNS while some 7000 patients with TRD have been denied access to VNS therapy by their payers.19 VNS has been available in the European Economic Area and in Canada as a therapy for depression for patients with TRD since 2001.

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